Beyond spermatogenesis: Additional roles of seminal fluid fatty acids in male fertility and age-related reproductive success

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Project Summary/Abstract In many animals, the seminal fluid plays a major role in male reproductive success. Proteins in the seminal fluid have significant effects on multiple features of male and female reproductive physiology. However, relatively little is known about a second major component of seminal fluid, lipids, beyond their roles as sperm membrane constituents. The overall objectives in this proposal are to i) identify differences in the lipidomic and transcriptomic profiles of seminal fluid in young and aged males; and ii) directly test how manipulating the lipid profile of seminal fluid impacts male reproductive success. This proposal will address the hypothesis that the seminal fluid lipidome influences male fertility and changes with age, thus contributing to the decline of aging-related reproductive success. This hypothesis is supported by the applicants’ published studies showing that fatty acids and related lipids in the seminal fluid of Drosophila males are essential for male fertility. Both transposon-mediated knockout and RNAi knockdown of a key fatty acid biosynthesis enzyme in the male ejaculatory bulb (EB), an organ that is not involved in spermatogenesis, causes a significant decrease in male fertility, strongly supporting the contribution of seminal fluid fatty acids to male reproductive success. In contrast to mammalian models, use of Drosophila allows seminal fluid lipids produced in the EB to be manipulated without interfering with spermatogenesis in the testes. Powerful genetic manipulation in combination with lipidomic and transcriptomic analysis will be used to pursue the following aims: Aim 1 of the proposal will test a prediction of the hypothesis that changes in the composition of seminal fluid fatty acids and other lipids accompany aging-related loss of fertility. Using multiple mass spectrometry methods, the seminal fluid lipidome will be characterized in young and old males in order to identify features of the lipid profile that correlate with high and low fertility. Aim 2 will test a second prediction of the hypothesis, that the expression of fatty acid synthesis genes in the EB changes in aging males, leading to a shift in fatty acid and related lipid composition in the seminal fluid. Transcriptomic analysis of the EB from young and old males followed by functional validation with genetic knockdown will identify genes that underlie age-related changes in seminal fluid lipid content. In Aim 3, a direct test of the hypothesis will be performed by assessing whether male fertility improves or declines upon genetic manipulation of the seminal fluid fatty acid content. The expected outcomes are significant because they are likely to identify new mechanisms that modulate male and female reproductive physiology and may point to previously unrecognized causes of idiopathic male infertility. The proposed study is innovative because it is expected to identify a new class of molecules and novel biochemical pathways that could be used to improve the diagnosis of infertility, enhance assisted reproductive technology, and treat aging-related decline in fertility.